Implantable polymeric device for sustained release of dopamine agonist

ABSTRACT

The present invention provides compositions, methods, and kits for treatment of Parkinson&#39;s disease and other conditions for which treatment with a dopamine agonist is therapeutically beneficial. The invention provides a biocompatible nonerodible polymeric device which releases dopamine agonist continuously with generally linear release kinetics for extended periods of time. Dopamine agonist is released through pores that open to the surface of the polymeric matrix in which it is encapsulated. The device may be administered subcutaneously to an individual in need of continuous treatment with dopamine agonist.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. provisional application No.60/459,315, filed on Mar. 31, 2003, which is incorporated herein byreference in its entirety.

TECHNICAL FIELD

The invention provides a nonbioerodible, polymeric device forsubcutaneous implantation and sustained release of dopamine agonist fortreatment of Parkinson's disease and other conditions for whichadministration of a dopamine agonist is therapeutically beneficial.

BACKGROUND OF THE INVENTION

Parkinson's disease, a progressive neurodegenerative disorder, ischaracterized by loss of neurons that synthesize and release dopamine.This loss of dopaminergic neurons manifests itself in symptoms such asrigidity, resting tremors (shaking), poverty of movement (akinesia),slowness of movement (bradykinesis), and changes in gait and posture.Treatment of Parkinson's disease generally is based on therapeuticadministration of substances that can compensate for the lack ofdopaminergic neurotransmission due to the loss of dopamine-secretingneurons. A classic treatment regime includes chronic oral administrationof levodopa, which is decarboxylated in the brain to form dopamine.Often, after several years of treatment with levodopa, abnormalitiesemerge, including involuntary movements during the “on” phase ofclinical improvement and re-emergence of Parkinson's-type symptomsduring “off” phases.

Apomorphine, an effective agonist at both dopamine receptors in thenervous system, has been used for treatment of Parkinson's disease inpatients that have become resistant to or have developed adverse sideeffects with associated with chronic levodopa therapy. Typically, due toits short duration of effectiveness, apomorphine is administered byrepeated subcutaneous injections or continuous parenteral infusion via apump. These means of administration are inconvenient, in the case ofsubcutaneous injection, and technically difficult, in the case of pumpadministration, especially for Parkinson's patients whose dexterity isimpaired due to the disease itself and the movements associated withchronic levodopa treatment. Apomorphine may also be administeredtransdermally (U.S. Pat. No. 5,562,917), intranasally (U.S. Pat. No.5,756,483), as a topically-applied gel (U.S. Pat. No. 5,939,094), orsublingually (U.S. Pat. No. 5,994,363). None of these methods permitscontinuous administration over long periods of time.

Dopamine agonists have also been used for treatment of parkinsonismwhich results from central nervous system injury by toxin exposure or adisease condition such as encephalitis, erectile dysfunction, restlessleg syndrome, and hyperprolactinemia.

There is a need for an improved means of administration that wouldpermit continuous dosing of dopamine agonists over an extended period oftime of several months or longer, without the adverse side effectsassociated with peaks and troughs in plasma levels due to discontinuousdosing, or reliance on cumbersome mechanical equipment such as a pump.

BRIEF SUMMARY OF THE INVENTION

The invention provides compositions (i.e., implantable polymericdevices), methods, and kits for administration of one or more dopamineagonists to a mammal in need thereof.

In one aspect, the invention provides an implantable device foradministration of a dopamine agonist to a mammal in need thereof. Theimplantable device includes at least one dopamine agonist encapsulatedin a biocompatible, nonerodible polymeric matrix. After subcutaneousimplantation in a mammal, an implantable device of the inventionreleases dopamine agonist continuously in vivo through pores that opento the surface of the matrix at a rate that results in a plasma level ofat least about 0.001, 0.005, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07,0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 5, or 10ng/ml in various embodiments. In some embodiments, an implantable deviceof the invention includes ethylene vinyl acetate (EVA) as abiocompatible, nonerodible polymer for formation of the polymericmatrix. In various embodiments, the vinyl acetate content of EVA usedfor preparation of the polymeric matrix is often about 2 to about 40,more often about 10 to about 35, most often about 30 to about 35%. Insome embodiments, the vinyl acetate content is about 33%. An implantabledevice of the invention includes about 10 to about 85% dopamine agonist.In some embodiments, the dopamine agonist is apomorphine, lisuride,pergolide, bromocriptine, pramipexole, ropinerole, or rotigotine. In oneembodiment, the dopamine agonist is apomorphine. The dopamine agonist isgenerally at least a dopamine D2 receptor agonist, but may also be anagonist for the D1 and/or D3 dopamine receptors. Implantable devicesoften release dopamine agonist continuously in vivo for at least about3, 6, 9, 12, 15, 18, 21, or 24 months. In some embodiments, implantabledevices of the invention are produced using an extrusion process,sometimes producing devices with dimensions of about 2 to about 3 mm indiameter and about 2 to about 3 cm in length, although other shapes andsizes are contemplated and are within the skill of the art. Often, animplantable device of the invention releases dopamine agonist at a rateof at least about 0.1 to about 10 mg/day at steady state in vitro or invivo. In various embodiments, the implantable devices release dopamineagonist at a rate of at least about 0.01, 0.05, 0.1, 0.5, 1, 2, 3, 4, 5,6, 7, 8, 9, or 10 mg/day in vitro or in vivo. In some embodiments, adopamine-containing implantable device may further include ananti-inflammatory agent, for example a steroid, a nonsteroidalanti-inflammatory drug (“NSAID”), or an antihistamine, and/or anantioxidant within the polymeric matrix.

In another aspect, the invention provides a method for administration ofa dopamine agonist to a mammal in need thereof. Methods of the inventioninclude subcutaneous administration of at least one implantable deviceas described above. In some embodiments, the methods includesubcutaneous implantation of a multiplicity of the devices. In methodsof the invention, the device or devices release dopamine agonist at asteady state level that is therapeutically effective for treatment of acondition for which administration of a dopamine agonist istherapeutically beneficial, for example, Parkinson's disease, toxin- ordisease-induced parkinsonism, erectile dysfunction, restless legsyndrome, or hyperprolactinemia. In some embodiments, the dopamineagonist is apomorphine, lisuride, pregolide, bromocriptine, pramipexole,ropinerole, or rotigotine. In one embodiment, the dopamine agonist isapomorphine. Typically, each device, or the combination of amultiplicity of devices, continuously releases at least about 0.001,0.005, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2,0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 5, 10, 25, 50, or 100 ng ofdopamine agonist per ml of plasma at steady state. Generally, eachdevice releases at least about 0.1 mg of dopamine agonist per day invitro. In various embodiments, one or a multiplicity of devices issubcutaneously implanted in an individual, for example, on the upperarm, the back, and/or the abdomen.

In some embodiments, one or more anti-inflammatory agents arecoadministered along with dopamine agonist. The anti-inflammatory agentmay be encapsulated within the same polymeric device as dopamine agonistor in a separate polymeric device that does not contain dopamineagonist, or may be administered via a different route, such as orally orvia injection, either simultaneously with implantation of the dopamineagonist-containing devices or at a different time, or on a differentschedule such as for example multiple dosing of an oral or injectableformulation. In various embodiments, the anti-inflammatory agent may bea steroid, a NSAID, and/or an antihistamine. In some embodiments, anantioxidant is incorporated into the dopamine agonist-containingpolymeric device and is coadministered along with dopamine agonist. Insome embodiments, the methods of the invention include administration ofanother substance in conjunction with administration of dopamine agonistvia an implanted polymeric device of the invention. Such substancesinclude, but are not limited to, levodopa, dopamine agonists,catechol-O-methyltranserase inhibitors, or monoamine oxidase inhibitors,administered orally or intravenously.

In another aspect, the invention provides a kit for use in a method ofadministration of a dopamine agonist to a mammal in need thereof. Kitsof the invention include at least one implantable device that includesdopamine agonist encapsulated in a biocompatible, nonerodible polymericmatrix, as described above, and instructions for use. In someembodiments, kits of the invention include a multiplicity of individualdopamine agonist-containing implantable devices.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts in vitro release of apomorphine over time. FIG. 1 showsthe average cumulative release of apomorphine HCl (“ApoH”) from implantsloaded with 50%, 60%, or 70% ApoH and washed for 30 minutes (FIG. 1A),60 minutes (FIG. 1B), or 120 minutes (FIG. 1C) in ethanol.

FIG. 2 depicts in vitro release of ApoH and loratidine (“LA”) over timefrom an implant loaded with 49% ApoH and 21% LA.

DETAILED DESCRIPTION OF THE INVENTION

The invention provides a biocompatible, nonerodible polymeric device,which permits controlled, sustained release of one or more dopamineagonists over extended periods of time when implanted subcutaneously inan individual in need of treatment.

Continuous release of a compound in vivo over an extended duration maybe achieved via implantation of a device containing the compoundencapsulated, i.e., dispersed, in a nonerodible polymeric matrix.Examples of implantable, nonerodible polymeric devices for continuousdrug release are described in, e.g., U.S. Pat. Nos. 4,883,666,5,114,719, and 5,601,835. Implantation of the device and extendedrelease of dopamine agonist improves compliance with dosing regimens,eliminating the need for repeated injections, ingestion of pills ortablets, or manipulations associated with a mechanical diffusion pump.An implantable, sustained-release device according to the presentinvention also permits achievement of more constant blood levels ofdopamine agonist than injectable or oral dosage forms, therebypermitting lower dosing levels than conventional means ofadministration, minimizing side effects, and improving therapeuticeffectiveness.

Devices of the invention include one or more non-bioerodible polymers.Such polymers release compounds at linear rates for extended timeperiods of several months or longer, in contrast to bioerodiblepolymers, which do not exhibit linear release kinetics due to formationof channels in the matrix as it erodes, resulting in increased releaserates over time. The present invention includes a biocompatible,nonerodible polymer that exhibits generally linear release kinetics fordopamine agonist in vivo, after an initial burst.

Implantable Polymeric Devices

The invention includes implantable devices for treatment of Parkinson'sdisease or other conditions for which administration of a dopamineagonists is therapeutically beneficial. Devices of the invention includeone or more dopamine agonists encapsulated in a polymeric, nonerodiblematrix.

“Dopamine agonist” as used herein refers to a compound which is capableof binding to one or more dopamine receptor subgroups, resulting inbeneficial therapeutic effect in an individual treated with the agonist.The dopamine agonists described herein typically are agonists for atleast the D2 subgroup of dopamine receptors, and may also be agonistsfor D1 and/or D3 receptors. In various embodiments, an implantabledevice of the invention includes apomorphine, lisuride, pergolide,bromocriptine, pramipexole, ropinerole, or rotigotine, or a combinationor two or more of these dopamine agonists. In one embodiment, theimplantable device includes apomorphine. “Apomorphine” refers toapomorphine and pharmaceutically acceptable salts thereof, such as forexample, apomorphine HCl (“ApoH”).

Incorporation of dopamine agonist into the polymeric matrix causes theformation of a series of interconnecting channels and pores that areaccessible to the surface for release of the drug. When implantedsubcutaneously, devices of the invention continuously release dopamineagonist for an extended period of time with a pseudo or near zero orderrelease rate. After an initial burst following implantation, releaserates are typically within about 10-20% of the steady state average.

As used herein, “nonerodible matrix” refers to a polymeric carrier thatis sufficiently resistant to chemical and/or physical destruction by theenvironment of use such that the matrix remains essentially intactthroughout the release period. The polymer is generally hydrophobic sothat it retains its integrity for a suitable period of time when placedin an aqueous environment, such as the body of a mammal, and stableenough to be stored for an extended period before use. The ideal polymermust also be strong, yet flexible enough so that it does not crumble orfragment during use. Nonerodible matrices remain intact in vivo forextended periods of time, typically months or years. Drug moleculesencapsulated in the matrix are released over time via diffusion throughchannels and pores in a sustained and predictable manner. The releaserate can be altered by modifying the percent drug loading, porosity ofthe matrix, structure of the implantable device, or hydrophobicity ofthe matrix, or by adding a hydrophobic coating to the exterior of theimplantable device.

Where appropriate, a coating that is impermeable to the drug is placedover at least a portion of the device to further regulate the rate ofrelease. For example, a coating of a nonerodible polymeric material,e.g., EVA, or a coating of a nonerodible polymeric material with a lowerdrug loading than the remainder of the implantable device, may be used.Such a coating may be formed, for example, by co-extrusion with thedevice.

Typically, ethylene vinyl acetate copolymer (EVA) is used as thepolymeric matrix, but other nonerodible materials may be used. Examplesof other suitable materials include silicone, hydrogels such ascrosslinked poly(vinyl alcohol) and poly(hydroxy ethylmethacrylate),acyl substituted cellulose acetates and alkyl derivatives thereof,partially and completely hydrolyzed alkylene-vinyl acetate copolymers,unplasticized polyvinyl chloride, crosslinked homo- and copolymers ofpolyvinyl acetate, crosslinked polyesters of acrylic acid and/ormethacrylic acid, polyvinyl alkyl ethers, polyvinyl fluoride,polycarbonate, polyurethane, polyamide, polysulphones, styreneacrylonitrile copolymers, crosslinked poly(ethylene oxide),poly(alkylenes), poly(vinyl imidazole), poly(esters), poly(ethyleneterephthalate), polyphosphazenes, and chlorosulphonated polyolefines,and combinations thereof.

Implantable devices of the invention are typically formulated withdopamine agonist loading of about 10% to about 85%. Devices are oftenformulated as compositions that include a polymeric matrix that includesEVA (33% acetate) and any of at least about 10, 20, 30, 40, 50, 55, 60,65, 70, 75, or 80 to about 85%, or any of about 10 to about 20, about 20to about 30, about 30 to about 40, about 40 to about 50, about 50 toabout 60, about 60 to about 70, about 70 to about 80, or about 80 toabout 85% dopamine agonist by weight. Devices may be produced using anextrusion process, wherein ground EVA is blended with dopamine agonist,melted, and extruded into rod-shaped structures. Rods are cut intoindividual implantable devices of the desired length, packaged, andsterilized prior to use. Other methods for encapsulating therapeuticcompounds in implantable polymeric, nonerodible matrices are well knownto those of skill in the art. Such methods include, for example, solventcasting (see, e.g., U.S. Pat. Nos. 4,883,666, 5,114,719, and 5,601,835).A skilled artisan would be able to readily determine an appropriatemethod of preparing such an implantable device, depending on the shape,size, drug loading, and release kinetics desired for a particular typeof patient or clinical indication.

Devices of the invention are suitable for sustained release of dopamineagonist for treatment of idiopathic Parkinson's disease or anothercondition for which administration of dopamine agonist istherapeutically beneficial, such as, for example, toxin- ordisease-induced parkinsonism, erectile dysfunction, restless legsyndrome, or hyperprolactinemia. As used herein, “sustained release”refers to the release of dopamine agonist such that the bloodconcentration remains within the therapeutic range but below toxiclevels for an extended duration. Devices of the invention generallyexhibit near zero-order pharmacokinetics in vivo, similar to kineticsachieved with an IV drip, but without the need for external medicalequipment and personnel associated with intravenous methods. Generally,after implantation, the devices release therapeutically effectiveamounts of dopamine for periods of several months up to one year orlonger.

Multiple implantable devices may be used, or the size and shape of thedevices may be modified, to achieve a desired overall dosage.Implantable devices are often about 0.5 to about 10, more often about1.5 to about 5, often about 2 to about 6, most often about 2 to about 3cm in length, and are often about 0.5 to about 7, more often about 1.5to about 5, most often about 2 to about 3 mm in diameter. An implantabledevice of the invention may release dopamine agonist in vitro or in vivoat a rate of about 0.01 to about 10, about 0.1 to about 10, about 0.25to about 5, or about 1 to about 3 mg/day in vitro or in vivo. Therelease rate of implantable devices may also be modified by changing thevinyl acetate content in the EVA polymer matrix. The vinyl acetatecontent is often about 2 to about 40, more often about 10 to about 35,most often about 30 to about 35% by weight. In one embodiment, the vinylacetate content is about 33% by weight.

In certain embodiments, devices of the invention may include othersubstances in addition to dopamine agonist to increase effectiveness oftreatment and/or reduce inflammation at the site of administration, orto prevent oxidation of dopamine agonist(s). For example, ananti-inflammatory agent, such as for example, a steroid, examples ofwhich include but are not limited to dexamethasone, triamcinolone,betamethasone, clobetasol, cortisone, hydrocortisone, or apharmaceutically acceptable salt thereof, or a nonsteroidalanti-inflammatory agent (“NSAID”), examples of which include but are notlimited to diclofenac potassium diclofenac sodium, diclofenac sodiumwith misoprostol, diflunisal, etodolac, fenoprofen calcium,flurbiprofen, ibuprofen, indomethacin, ketoprofen, meclofenamate sodium,mefenamic acid, meloxicam, nabumetone, naproxen, naproxen sodium,oxaprozin, piroxicam, sulindac, tolmetin, COX-2 inhibitors (e.g.,celecoxib, rofecoxib, valdecoxib), acetylated salicylates (e.g.,aspirin), nonacetylated salicylates (e.g., choline, magnesium, andsodium salicylates, salicylate), and/or an antihistamine, examples ofwhich include but are not limited to loratadine (“LT”), astemizole,cetrizine dihydrochloride, chlorpheniramine, dexochlorpheniramine,diphenhydramine, mebhydrolin napadisylate, pheniramine maleate,promethazine, or terfenadine, may be encapsulated within an implant toprevent or reduce local inflammation at the site of administration. Anyof these agents, or a combination, may be included in the sameimplant(s) as dopamine agonist or alternatively, may be incorporatedinto one or more separate implants that do not include dopamine agonist.An antioxidant, e.g., ascorbic acid, sodium metabisulfite, glutathione,may be included in the same implant as dopamine agonist to prevent orreduce oxidation of dopamine agonist during preparation, storage, and/oradministration of the implant.

METHODS OF THE INVENTION

The invention provides methods for treatment of idiopathic Parkinson'sdisease or toxin- or disease-induced parkinsonism, or any othercondition for which administration of a dopamine agonist istherapeutically beneficial, e.g., erectile dysfunction, restless legsyndrome, or hyperprolactinemia. “Parkinsonism” as used herein includesconditions resulting from injury to the central nervous system thatcause an individual to exhibit symptoms similar to those of Parkinson'sdisease. Parkinsonism may result, for example, from toxin exposure, forexample, carbon monoxide or manganese poisoning or MPTP administration,or from a disease condition such as encephalitis.

Methods of the invention include subcutaneous administration of one ormore polymeric implantable devices which each include one or moredopamine agonists encapsulated within a biocompatible, nonerodiblepolymeric matrix, e.g., EVA, and release of the dopamine agonist(s) in acontrolled manner over an extended period of time through multiple poresthat open to the surface of the implantable device(s). Often,implantable devices are produced via an extrusion process, as describedabove.

In various embodiments, the method includes administration ofapomorphine, lisuride, pergolide, bromocriptine, pramipexole,ropinerole, or rotigotine, or a combination or two or more of thesedopamine agonists. A combination of dopamine agonists may beadministered from the same implantable device(s) or may be administeredfrom separate implantable devices. In one embodiment, the methodincludes administration of apomorphine.

Implantable devices are administered by subcutaneous implantation to anindividual in need of treatment with a dopamine agonist. As used herein,“individual” refers to a mammal, such as a human, in need of treatmentfor Parkinson's disease or parkinsonism, or another condition for whichdopamine administration is therapeutically beneficial. Generally,implantable devices are administered by subcutaneous implantation atsites including, but not limited to, the upper arm, back, or abdomen ofan individual. Other suitable sites for administration may be readilydetermined by a medical professional. Multiple implantable devices maybe administered to achieve a desired dosage for treatment.

Typically, in a treatment method of the invention, an implantable deviceor a multiplicity of devices is administered that will release dopamineat a rate that will maintain a therapeutically effective plasma levelfor an extended period of time of at least about 3, 6, 9, 12, 15, 18,21, or 24 months. Often, the duration of implantation, with continuousrelease of dopamine agonist, is from about 3 months to about 2 years,about 3 months to about 1 year, about 3 months to about 9 months, orabout 3 months to about 6 months.

The desired dosage rate will depend upon factors such as the underlyingcondition for which dopamine agonist is being administered, and thephysiology of a particular patient, but will be readily ascertainable tophysicians. Dopamine agonist is desirably released from one or amultiplicity of implanted devices at a rate that maintains plasma levelsof the drug(s) at a therapeutically effective level. Maintenance ofdopamine agonist at a fairly constant plasma level often permits dosingat a lower level than with other therapies, such as oral administration.

As used herein, “therapeutically effective amount” or “therapeuticallyeffective level” refers to the amount of dopamine agonist that willrender a desired therapeutic outcome, e.g., a level or amount effectiveto reduce symptoms of Parkinson's disease and/or increase periods oftherapeutic effectiveness (“on” periods) for a patient undergoingchronic dopaminergic therapy for idiopathic Parkinson's disease ortoxin- or disease-induced parkinsonism, or beneficial treatment, i.e.,reduction or alleviation of adverse or undesirable symptoms of acondition treatable with a dopamine agonist, such as erectiledysfunction, restless leg syndrome, or hyperprolactinemia. For treatmentof Parkinson's disease or parkinsonism, effectiveness is oftenassociated with reduction in “on”/“off” fluctuations associated with aparticular Parkinson's disease treatment regime, such as for example,chronic levodopa administration. An amount that is “therapeuticallyeffective” for a particular patient may depend upon such factors as apatient's age, weight, physiology, and/or the particular symptoms orcondition to be treated, and will be ascertainable by a medicalprofessional.

When multiple devices are administered, the combination of the devicesreleases dopamine agonist at a rate that will achieve a therapeuticallyeffective plasma level. Often, a desirable steady-state plasma level ofdopamine agonist in methods of the invention is in the range of about0.005 to about 100 ng/ml, about 0.01 to about 100 ng/ml, about 0.05 toabout 0.65 ng/ml, about 0.2 to about 0.65 ng/ml, about 0.2 to about 45ng/ml, or about 1 to about 20 ng/ml. In various embodiments, animplantable device of the invention may release dopamine agonist in vivoat a rate that results in a plasma level of at least about 0.001, 0.005,0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3,0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 5, or 10 ng/ml at steady state. A totalrelease rate from one or a multiplicity of implanted devices thatresults in delivery of a therapeutically effective amount of dopamineagonist on a daily basis is typically about 0.01 to about 10 mg/day,often about 0.25 to about 5 mg/day, sometimes about 1 to about 3 mg/day,but may be modified depending upon the symptomology involved and theparticular patient being treated. For example, for treatment ofParkinson's disease with apomorphine or another dopamine agonistdescribed herein, one or more implantable devices may be used with atotal release rate of about 0.01 to about 10 mg/day, about 0.25 to about5 mg/day, or about 1 to about 3 mg/day apomorphine.

It is anticipated that the implantable devices of the invention willalleviate compliance difficulties, as described above. In methods of theinvention, long term continuous release of dopamine agonist generallyreduces or eliminates the peaks and troughs of blood concentrationassociated with other formulations such as oral or injectable dosageforms, which permits dosing at a lower level than traditional treatmentregimens. This often reduces or alleviates adverse side effectsassociated with higher dosages, for example, nausea, vomiting,orthostatic hypotension, hallucinations, delirium, or dyskinesia.

In some methods of the invention, dopamine is administered via animplantable device of the invention in conjunction with another therapy.For example, for Parkinson's or parkinsonism, dopamine agonist may beadministered via implantable devices of the invention in conjunctionwith levodopa, dopamine agonists, catechol-O-methyltransferase (COMT)inhibitors, or monoamine oxidase (MAO) inhibitors, administered orallyor intravenously.

Some methods of the invention include coadministration of anothersubstance or substances in conjunction with dopamine agonist. Forexample, an anti-inflammatory agent or agents, such as a steroid, aNSAID, and/or an antihistamine, may be administered via an implantabledevice, by local, systemic, or subcutaneous injection, or orally, inconjunction with administration of dopamine agonist in an implantabledevice of the invention, to reduce or prevent inflammation caused by theagonist(s) at the site of administration of the implant. When theanti-inflammatory agent(s) is administered via an implantable device, itmay be included in the same implant as dopamine agonist or in a separateimplantable device. An implantable device may include one or more of theanti-inflammatory agents described above. The amount ofanti-inflammatory agent administered is an amount expected to beeffective to reduce local inflammation associated with administration ofdopamine agonist in an implanted device of the invention.

In some methods of the invention, an antioxidant may be included in thedopamine agonist implant to prevent oxidation of the dopamine agonist(s)during preparation, storage, and/or administration of the implant.Generally, the amount of antioxidant incorporated into the implant is anamount sufficient to prevent oxidation of at least a portion, typicallysubstantially all of the dopamine agonist in the implant.

Methods of the invention may be used to treat any subpopulation ofParkinson's disease patients, including, for example, “de novo”patients, e.g, patients who have not previously received treatment,“early stage” patients, e.g., patients who have been treated for a shortperiod of time with another therapy such as levodopa administration butwho are not exhibiting adverse side effects from the other therapy,“late stage” patients, e.g., patients who are exhibiting side effectsassociated with chronic treatment with another therapeutic substancesuch as levodopa, and “fluctuators,” e.g., patients for whom treatmentwith another substance such as levodopa fluctuates in effectiveness inan “on”/“off” manner.

Methods of the invention may be used, for example, to decrease motorfluctuations and dyskinesias for treatment of “late stage” patients withmotor fluctuations. Continuous dosing via an implantable device of theinvention may decrease “off” time and decrease dyskinesias. The methodsmay also be used, for example, to prevent motor fluctuations anddyskinesias in “early stage” patients who are undergoing pharmacologictherapy for the first time. This group often received monotherapy with adopamine agonist. Administration via an implantable device of theinvention may allow continuous dopamine agonist receptor stimulation,thus decreasing the risk of motor fluctuations and dyskinesias later intreatment. The methods may also be used, for example, to prevent motorfluctuations and dyskinesias in patients on dopamine agonist monotherapywho require 1-dopa supplementation. Since it is difficult to administer1-dopa with linear dosing kinetics, and motor complications often emergewhen 1-dopa is administered, continuous dosing via the implantabledevices of the invention may allow continuous dopamine agonist receptorstimulation and decrease the risk of motor fluctuations and dyskinesiasat this point in treatment.

Kits

The invention also provides kits for use in treatment of Parkinson'sdisease or another condition for which dopamine agonist administrationis therapeutically beneficial, as described above. The kits contain atleast one implantable, nonerodible device of the type herein described,capable of delivering long-term therapeutic levels of dopamine agonist,in suitable packaging, along with instructions providing information tothe user and/or health care provider regarding subcutaneous implantationand use of the system for treating a condition for which dopamineagonist administration is therapeutically beneficial, such as, forexample, Parkinson's disease, toxin- or disease-induced parkinsonism,erectile dysfunction, restless leg syndrome, or hyperprolactinemia. Kitsmay also include literature discussing performance of the implantabledevices of the invention.

In various embodiment, kits of the invention may include implantabledevices that include apomorphine, lisuride, pergolide, bromocriptine,pramipexole, ropinerole, or rotigotine, or combinations of any of thesedopamine agonists in the same or separate polymeric implants. In oneembodiment, a kit includes one or more implantable devices that includeencapsulated apomorphine.

Kits may include a delivery system, i.e., one or a multiplicity ofimplantable devices, capable of providing sustained release oftherapeutic levels of dopamine agonist, e.g., about 0.005 to about 100ng/ml, about 0.01 to about 100 ng/ml, about 0.05 to about 0.65 ng/ml,about 0.2 to about 0.65 ng/ml, about 0.2 to about 45 ng/ml, or about 1to about 20 ng/ml, for at least about 3 months. Kits of the inventionmay include implantable devices each capable of in vivo release ofdopamine agonist such that a plasma level of at least about 0.001,0.005, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2,0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 5, 10, 25, 45, or 100 ng/ml isachieved at steady state. Kits of the invention may include a deliverysystem capable of releasing about 0.1 to about 10, about 0.25 to about5, or about 1 to about 3 mg/day dopamine agonist in vitro or in vivo.

The device(s) in a kit may include one or more substances in addition todopamine agonist, such as one or more an anti-inflammatory agents, suchas a steroid, NSAID, or antihistamine, and/or an antioxidant.

In kits of the invention, an implantable device or devices may bepreloaded into an apparatus or apparatuses suitable for subcutaneousimplantation of the device(s) into a patient, such as, for example,syringes or trocars.

EXAMPLES

The following examples are intended to illustrate but not limit theinvention.

Example 1 Materials and Methods

Materials

The following materials were used:

-   -   Apomorphine HCl, supplied by Hawkins, Inc.    -   Triamcinolone Acetonide, supplied by Spectrum    -   Glutathione, supplied by Aldrich, St. Louis, Mo.    -   Ethylene vinyl acetate copolymer, 33% vinyl acetate, supplied by        Southwest Research Institute, San Antonio, Tex.    -   Methanol, ChromAR HPLC Grade, supplied by Mallinckrodt, St.        Louis, Mo.    -   Acetonitrile, ChromAR HPLC Grade, supplied by Mallinckrodt, St.        Louis, Mo.    -   Trifluoro Acetic Acid, 99%, Spectrochemical grade, supplied by        Aldrich Chemicals, St. Louis, Mo.    -   Sodium Dodecyl Sulfate, 99%, supplied by EM Science    -   Ethanol, supplied by Mallinckrodt, St. Louis, Mo.        HPLC Assays

An HPLC method was used to determine the rate of in vitro release ofapomorphine HCl (“ApoH”) or loratidine (“LA”) from the implants.Chromatography was performed using a Zorbax SB-C 18 (250 mm×4.6 mm)column and 60% 0.1 trifluoro acetic acid in water, 15% methanol, 25%acetonitrile as the mobile phase, and a flow rate of 1 ml/min. Theinjection volume was 10 μl. Detection was accomplished by means of aUV/VIS detector at a wavelength of 270 nm. Instrument control and dataacquisition were facilitated using a Waters Millennium (V 2.15) softwarepackage. The external calibration was obtained using ApoH or LA standardsolutions.

Preparation of Implantable Devices

Implantable devices were prepared using an extrusion process in aMicrotruder device (Rancastle, RC-025-CF-RF). In order to facilitatefeeding into the extruder and to enable mixing of apomorphine and othersubstances to be incorporated into the implants, EVA was ground intosmaller particle sizes prior to extrusion. The extrusion process wasperformed under argon gas to prevent oxidation of apomorphine. Allblends of copolymer and drug(s) were prepared by rolling in a 120 mlamber bottle for approximately 10 minutes. The blend was then fedthrough the Microtruder. Parameters that were used for extrusion ofApoH/EVA implants are shown in Table 1, and parameters used forextrusion of implants that included triancinolone (“TA”), glutathione(“GSH”), and/or LA are shown in Table 2. TABLE 1 Parameters forExtrusions of APO/EVA Implants Formulations Zone Temperature (° F.)(Weight Percentage) 1 2 3 Die APO/EVA 180 185 190 185 (50:50) APO/EVA185 195 200 195 (60:40) APO/EVA 215 230 240 250 (70:30)

TABLE 2 Parameters for Extrusions of APO/EVA/TA/GSH ImplantsFormulations Zone Temperature (° F.) (Weight Percentage) 1 2 3 DieAPO/EVA 190 195 205 200 (60:40) APO/TA/EVA 215 230 240 248 (60:10:30)APO/TA/GSH/EVA 215 235 245 255 (60:8:2:30) APO/LA/EVA 215 226 232 230(49:21:30)

All of the materials used during the extrusion process were protectedfrom light to prevent light-catalyzed oxidation. The extruder was set tothe required temperatures and allowed to reach equilibrium. After theextruder reached equilibrium, approximately 15 grams of blend wereextruded and cut into 18-inch rods. The diameter was measured at 2.4 mm.The rods were then cut to the desired implant length of 26 mm.

The implants were then washed by placing them on an aluminum screen andimmersing them in ethanol (approximately 50 ml per implant). Theimplants were washed for approximately 30, 60, or 120 minutes in theethanol bath. The washed implants were air dried for 10 minutes and ovendried at 40° C. for 1 hour before drying in a vacuum over for 24 hoursat 30° C. The implants were packaged into 20 ml glass vials in thepresence of argon gas, sealed, and then sterilized by gamma irradiation.

Example 2 In Vitro Characterization of Extruded Implantable Devices

Extruded rods prepared as described above were characterized for totaldrug load and for rate of drug release.

Assessment of Drug Loading

Implants prepared with 70% ApoH:30% EVA were cut into 2 mm pieces,accurately weighed, and placed into 250 ml volumetric flasks.Approximately 200 ml of methanol was added to each flask and thesolution was continuously stirred at room temperature until the implantswas dissolved. The solution was then assayed for drug content.

The average ApoH content for unwashed, washed, and sterilized rods wasbetween 66.9 and 67.9% ApoH, corresponding to 95.6 to 97% recovery.

Assessment of Drug Release

Experiments were performed to determine the rate of apomorphine releasedfrom the extruded rods. The medium for these studies was 0.5% sodiumdodecyl sulfate (“SDS”). Preweighed rods were placed in 100 ml screw capjars containing 50 ml of medium and placed on an orbital shaker. Theorbital shaker was housed in an incubator maintained at 37° C. Samplingwas performed by replacing the medium periodically. The samples obtainedwere analyzed by HPLC.

FIG. 1 shows the release of apomorphine from implants that have beenloaded with 50, 60, or 70% apomorphine and that have been washed for 30,60, or 120 minutes. The in vitro release data indicate that the implantsreleased a high amount of apomorphine during the first few days, thenreached steady state between about 3 and 7 days. As the drug loadincreased, the rate of release ApoH increased for implants washed up toone hour. The data from implants washed for 2 hours showed nosignificant difference in release rate for the different drug loadinglevels.

FIG. 2 shows the release of ApoH and LA from a 49% ApoH/21% LA/EVAimplant. Both ApoH and LA reached steady state release rates withinabout 3 days.

Example 3 In Vivo Evaluation of Drug Loaded Implantable Devices

Four MPTP-lesioned, L-DOPA-naïve cynomolgus monkeys were administeredthree 2.4 mm diameter×2.6 cm length rod-shaped implantable devicesprepared as described above, each containing 33% vinyl acetate andloaded with 98 mg+10% apomorphine HCl (68.5% apomorphine). Devices wereimplanted between the shoulder blades using a trocar. For comparison,three additional MPTP-lesioned, L-DOPA-naïve monkeys received pulsatiledaily subcutaneous injections of apomorphine at a dosage of 0.2 mg/kg,which is the minimally-effective dose to achieve “ON” status in theanimal.

All of the monkeys that received apomorphine implants were continuouslyin an “ON” state within one day after implantation, with an averagesteady state apomorphine level of approximately 0.5-1.0 ng/ml achievedafter an initial burst. In contrast, animals that received pulsatileinjections were “ON” for only approximately 90 minutes after eachadministration of apomorphine.

After 8.3 days (range 7-10) of daily apomorphine injections, all animalsin the pulsatile injection group developed dyskinesias. However, in theimplant group, no animal developed dyskinesia for the duration of thetreatment (up to six months). The apomorphine EVA implants providedcontinuous plasma levels of apomorphine, allowing for continuousstimulation of striatal dopaminergic receptors without onset ofdyskinesia, for the six month duration of the evaluation.

Although the foregoing invention has been described in some detail byway of illustration and examples for purposes of clarity ofunderstanding, it will be apparent to those skilled in the art thatcertain changes and modifications may be practiced without departingfrom the spirit and scope of the invention. Therefore, the descriptionshould not be construed as limiting the scope of the invention, which isdelineated by the appended claims.

All publications, patents, and patent applications cited herein arehereby incorporated by reference in their entirety.

1. An implantable device for administration of a dopamine agonist to amammal in need thereof, comprising a dopamine agonist and abiocompatible, nonerodible polymeric matrix, wherein said dopamineagonist is encapsulated within said matrix, and wherein when saidimplantable device is implanted subcutaneously in said mammal, saiddopamine agonist is continuously released in vivo over a sustainedperiod of time through pores that open to the surface of said matrix ata rate that results in a plasma level of at least about 0.01 ng/ml atsteady state.
 2. An implantable device according to claim 1, wherein thepolymeric matrix comprises ethylene vinyl acetate copolymer (EVA).
 3. Animplantable device according to claim 2, wherein said EVA comprisesabout 33% vinyl acetate.
 4. An implantable device according to claim 1,comprising about 10 to about 85% dopamine agonist.
 5. An implantabledevice according to claim 4, wherein said dopamine agonist is selectedfrom the group consisting of apomorphine, lisuride, pergolide,bromocriptine, pramipexole, ropinerole, and rotigotine.
 6. Animplantable device according to claim 5, wherein said dopamine agonistis apomorphine.
 7. An implantable device according to claim 1, whereinthe sustained period of time is at least about 3 months.
 8. Animplantable device according to claim 1, wherein the implantable deviceis produced by an extrusion process.
 9. An implantable device accordingto claim 8, comprising dimensions of about 2 to about 3 mm in diameterand about 2 to about 3 cm in length.
 10. An implantable device accordingto claim 9, wherein said implantable device releases about 0.1 to about10 mg of dopamine agonist per day in vitro at steady state.
 11. Animplantable device according to claim 1, further comprising ananti-inflammatory agent encapsulated within said matrix.
 12. Animplantable device according to claim 11, wherein said anti-inflammatoryagent is a steroid.
 13. An implantable device according to claim 11,wherein said anti-inflammatory agent is a nonsteroidal anti-inflammatorydrug (“NSAID”).
 14. An implantable device according to claim 11, whereinsaid anti-inflammatory agent is an antihistamine.
 15. An implantabledevice according to claim 1, further comprising an antioxidantencapsulated within said matrix.
 16. An implantable device foradministration of a dopamine agonist to a mammal in need thereof,comprising a dopamine agonist and a biocompatible, nonerodible polymericmatrix, wherein said dopamine agonist is encapsulated within saidmatrix, and wherein when said implantable device is subcutaneouslyimplanted in a mammal, said dopamine agonist is continuously released invivo over a sustained period of time through pores that open to thesurface of said matrix at a rate of at least about 0.1 mg of dopamineagonist per day at steady state.
 17. An implantable device according toclaim 16, wherein the polymeric matrix comprises EVA.
 18. An implantabledevice according to claim 17, wherein said EVA comprises 33% vinylacetate.
 19. An implantable device according to claim 16, comprisingabout 10 to about 85% dopamine agonist.
 20. An implantable deviceaccording to claim 16, wherein said dopamine agonist is selected fromthe group consisting of apomorphine, lisuride, pergolide, bromocriptine,pramipexole, ropinerole, and rotigotine.
 21. An implantable deviceaccording to claim 20, wherein said dopamine agonist is apomorphine. 22.An implantable device according to claim 16, wherein the sustainedperiod of time is at least about 3 months.
 23. An implantable deviceaccording to claim 16, wherein the implantable device is produced by anextrusion process.
 24. An implantable device according to claim 16,further comprising an anti-inflammatory agent encapsulated within saidmatrix.
 25. An implantable device according to claim 24, wherein saidanti-inflammatory agent is a steroid.
 26. An implantable deviceaccording to claim 24, wherein said anti-inflammatory agent is a NSAID.27. An implantable device according to claim 24, wherein saidanti-inflammatory agent is an antihistamine.
 28. An implantable deviceaccording to claim 18, further comprising an antioxidant encapsulatedwithin said matrix.
 29. A method for administration of a dopamineagonist to a mammal in need thereof, the method comprising administeringat least one implantable device subcutaneously, wherein each of said atleast one implantable devices comprises a dopamine agonist encapsulatedwithin a biocompatible, nonerodible polymeric matrix, wherein saiddopamine agonist is continuously released in vivo from each of said atleast one implantable devices over a sustained period of time throughpores that open to the surface of said matrix at a rate that results ina plasma level of at least about 0.01 ng/ml at steady state.
 30. Amethod according to claim 29, wherein said at least one implantabledevice comprises a multiplicity of individual implantable devices, andwherein the combination of said implantable devices continuouslyreleases dopamine agonist in vivo over a sustained period of time at arate that results in a plasma level of at least about 0.05 ng/ml atsteady state.
 31. A method according to claim 29, wherein the polymericmatrix comprises EVA.
 32. A method according to claim 31, wherein saidEVA comprises about 33% vinyl acetate.
 33. A method according to claim29, wherein each of said at least one implantable devices comprises atabout 10 to about 85% dopamine agonist.
 34. A method according to claim33, wherein said dopamine agonist is selected from the group consistingof apomorphine, lisuride, pergolide, bromocriptine, pramipexole,ropinerole, and rotigotine.
 35. A method according to claim 34, whereinsaid dopamine agonist is apomorphine.
 36. A method according to claim29, wherein said mammal has Parkinson's disease.
 37. A method accordingto claim 29, wherein said mammal has toxin- or disease-inducedparkinsonism.
 38. A method according to claim 29, wherein said mammalhas a condition selected from the group consisting of erectiledysfunction and restless leg syndrome.
 39. A method according to claim29, wherein the sustained period of time is at least about 3 months. 40.A method according to claim 29, wherein each of said at least oneimplantable devices is produced by an extrusion process.
 41. A methodaccording to claim 40, wherein each implantable device comprisesdimensions of about 2 to about 3 mm in diameter and about 2 to about 3cm in length.
 42. A method according to claim 41, wherein eachimplantable device releases at least about 0.1 mg of dopamine agonistper day in vitro.
 43. A method according to claim 29, wherein each ofsaid at least one implantable devices is subcutaneously implanted at asite selected from the group consisting of the upper arm, the back, andthe abdomen.
 44. A method according to claim 29, further comprisingadministration of an anti-inflammatory agent.
 45. A method according toclaim 44, wherein said anti-inflammatory agent is encapsulated in atleast one of said at least one implantable devices.
 46. A methodaccording to claim 44, wherein said anti-inflammatory agent isencapsulated within a biocompatible, nonerodible polymeric matrix thatdoes not comprise said dopamine agonist, and wherein said methodcomprises administration of said polymeric matrix comprising saidanti-inflammatory agent subcutaneously.
 47. A method according to claim44, wherein said anti-inflammatory agent is administered via a routeselected from the group consisting of local injection, systemicinjection, subcutaneous injection, and oral administration.
 48. A methodaccording to claim 44, wherein said at least one implantable devicesfurther comprises an antioxidant.
 49. A kit comprising at least oneimplantable device comprising a dopamine agonist encapsulated within abiocompatible, nonerodible polymeric matrix, wherein when said at leastone implantable device is implanted subcutaneously in a mammal, saiddopamine agonist is continuously released in vivo from each of said atleast one implantable devices over a sustained period of time throughpores that open to the surface of said matrix at a rate that results ina plasma level of at least about 0.01 ng/ml at steady state andinstructions for use in a method of administration of a dopamine agonistto a mammal in need thereof.
 50. A kit according to claim 49, whereinsaid at least one implantable device comprises a multiplicity ofindividual implantable devices, and wherein when the combination of saidimplantable devices is implanted subcutaneously in a mammal, saidimplantable devices continuously release dopamine agonist in vivo over asustained period of time at a rate that results in a plasma level of atleast about 0.05 ng/ml at steady state.
 51. A kit according to claim 49,wherein said implantable device releases dopamine agonist at a rate ofat least about 0.1 mg per day in vitro.
 52. A kit according to claim 49,wherein each of said implantable devices comprises EVA.
 53. A kitaccording to claim 52, wherein said EVA comprises about 33% vinylacetate.
 54. A kit according to claim 49, wherein each of saidimplantable devices comprises about 10 to about 85% dopamine agonist.55. A kit according to claim 54, wherein said dopamine agonist isselected from the group consisting of apomorphine, lisuride, pergolide,bromocriptine, pramipexole, ropinerole, and rotigotine.
 56. A kitaccording to claim 55, wherein said dopamine agonist is apomorphine.